Although novel agents have increased the survival of multiple myeloma (MM) patients, the ability of cancer cells to develop different mechanisms of resistance to therapeutic treatments has provided the scientific rationale to use new regimens that overcome these mechanisms. Despite the significant anti-MM activity of daratumumab (Dara), an increasing number of patients have exhibited relapsing disease with more aggressive features. Although CAR T cell therapy is now considered one of few therapeutic options for Dara-relapsing patients, relapse after CAR T cell therapy, as seen in MM and other cancers, is also an unfortunate scenario. Our preclinical data show that the radioactive antibody lutetium-177-Dara (177Lu-Dara) eliminates MM cells in mice bearing systemic MM disease, but that the curative doses of radioimmunotherapy (RIT) are toxic and eventually lethal. Our data also show that, although the anti-CS1 CAR T-treated MM mice have a significantly longer survival compared to control groups, MM cells are not completely eradicated, and the animals relapse. Thus, CS1 directed CAR-T therapy combined with lower dose CD38-directed RIT may have a beneficial effect in treating relapsing MM. To test this hypothesis, the team will determine the optimal non-toxic effective RIT dose as a single agent and the extent to which this dose is more effective when combined with CAR T cell therapy. The efficacy of treatment depends on a multitude of factors such as the disease burden, bone marrow (BM) toxicity, dose of RIT, dose of anti-CS1 CAR-T cells, and the scheduling and the frequency of the proposed therapies. To navigate through these myriad factors and deliver an optimal therapeutic strategy requires a sound understanding of the dynamics involved in each of the therapeutic options. In Specific Aim 1, the anti-MM dose of Dara-directed RIT will be optimized to achieve minimal BM associated toxicity. Extensive preclinical studies using DOTA-Dara labeled with two clinical relevant radionuclides, 177Lu and Actinium-225, will be conducted in an MM-engrafted mouse model. In Specific Aim 2, the antitumor activity of combining Dara RIT and CS1 CAR T cells will be evaluated to achieve complete disease eradication with minimal BM toxicity. The team will conduct in vivo combinatorial studies using radiolabeled Dara and CS1 CAR T cells at different doses and administration schedules in order to maximize MM killing activity and T cell immune activation. In Specific Aim 3, the group will develop a mathematical model to predict the efficacy of combined RIT and CS1 CAR-T therapy. Dara- directed RIT optimization studies and in vivo combinatorial studies will be used to parameterize radiobiological and ordinary differential equation based models. The developed modeling framework will be use to study and predict outcomes of different therapeutic combinations. These studies will define the optimum therapeutic dose of radiolabeled Dara as a single agent and in combination with CS1 CAR T cells with minimal toxicity. Because Dara-relapsing patients maintain expression of CS1 and CD38, it is believed that our therapeutic approach has the potential to treat patients for which novel interventions are highly needed.